Idiopathic Parkinson's disease (PD) affects 1-2% of the population over 60 and results in progressive disability for many patients. While most patients with PD initially respond well to dopamine (DA)-mimetic agents, many develop progressive refractoriness and/or unpredictable swings in response to these drugs. Multiple postmortem biochemical studies of PD brain indicate that basal ganglia pathways which utilize gamma-aminobutyric acid (GABA) are deficient in addition to the marked loss of DA function pathognomonic of PD. Two recent clinical trials have reported improvement in PD patients given concomitant GABA agonist (progabide) with DA-mimetic drugs. Animal studies from our laboratory have shown marked potentiation of motor behavior (contralateral turning) in rats with unilateral striatal DA loss given GABA-mimetic drugs prior to DA agonist. The thrust of the present proposal is to define the neurochemical mechanism responsible for this GABA-mimetic effect. Experiments in this proposal will test the hypothesis that D1 and D2 DA receptor activation in striatum (D1, D2) and ipsilateral nigra (D1) alter release of GABA and substance P (sub P) in both similar and different ways, and that low doses of GABA-mimetic drugs preferentially lower the release of nigral sub P. Regional microdialysis of nigra reticulata combined with drug injection into ipsilateral striatum in rats with unilateral striatal DA loss will allow this hypothesis to be tested in a rigorous fashion. The results of these experiments will allow neurochemical correlates to be drawn to our behavioral observations.